Compound Metformin/Glipizide Bilayer Extended Release Tablets: Development and in Vitro Release

Aim In this study, compound metformin/glipizide bilayer extended release tablets were formulated with hydroxypropyl methylcellulose （HPMC） by wet granulation technique in order to tackle the problems associated with the muhidrug therapy of non-insulin dependent diabetes mellitus. Me^ls High-dose metformin is difficult to formulate into a tablet dosage form due to its poor compressibility and compactibility. In this study, the way to overcome the difficulty was to utilize stearic alcohol to prepare the tablet formulation. The influences of viscosity, amount of HPMC, and weight of fillers were investigated. The optimal formulation had acceptable physicochemical properties and released metformin and glipizide over 10 h. Results The data of metformin obtained from in vitro release fitted Higuchi kinetics best, while the release of glipizide in vitro was found to follow zero kinetics. Conclusion Compound metformin/glipizide bilayer extended release tablets have been successfully developed.

Glipizide对非胰岛素依赖型糖尿病患者胰岛素敏感性的影响

用微小模型方法评价了 Glipizide 治疗前后6例 NIDDM 患者胰岛素敏感性(SI)的变化,同时观察了糖的自身效应(SG)、糖的下降速率(KG)、0～20分钟曲线下胰岛素释放面积(Iarea 0～20min)、空腹血糖(FBG)、空腹胰岛素(FINS),结果发现 NIDDM 患者治疗前 SI、SG、KG、Iarea 0～20min 均较正常对照组低,FBG 较对照组高,用 Glipizide 治疗2周后,FBG 降低,SI、SG、KG、Iarea 0～20min 均增加,说明 Glipizide 不仅具有刺激胰岛β细胞分泌的能力,同时具有胰腺外作用,改善胰岛素的敏感性及糖的自身效应。

Mechanism of Drug Release from Compound Metformin/Glipizide Elementary Osmotic Pump Tablets

In previous studies, compound mefformin/glipizide was developed. Aim To discover the mechanism of drug release from factors influencing drug release from dosage form （the semi-permeable cry orifice） were investigated. Results The influx of water that elementary osmotic pump tablet it. Methods Three rate-limiting membrane, tablet core and delivpassed the osmotic pump tablet was almost equal to the metformin release rate, while it was greatly less than the drug dissolution rate from tablet core. The size of orifice from 0. 4 mm to 0.8 mm had no influence on drug release. The osmotic pressure of tablet core was mainly caused by mefformin. Conclusion From the developed model of osmotic pump systems, it can be seen that only the water influx through the membrane is a rate-limiting step, not tablet core dissolution rate and solution influx, and only when the core dissolution rate is equal to the solution influx, the zero order release is seen in the osmotic pump systems.

Investigation of molecular aggregation mechanism of glipizide/cyclodextrin complexation by combined experimental and molecular modeling approaches

Cyclodextrin complexation is a wise strategy to enhance aqueous solubility of waterinsoluble drugs.However,the aggregation mechanism of drug-cyclodextrin complexes is still unclear.This research aimed to investigate the molecular aggregation mechanism of glipizide/cyclodextrin complexation by the combination of experimental and modeling methods.Binding free energies between glipizide and cyclodextrins from modeling calculations were higher than those by the phase solubility diagram method.Both experimental and modeling results showed that methylated-β-cyclodextrin exhibited the best solubilizing capability to glipizide.Size-measurement results confirmed the aggregation between glipizide and all four cyclodextrins in high concentrations.Glipizide/γ-cyclodextrin and glipizide/β-cyclodextrin complexes showed stronger aggregation trend than HP-β-cyclodextrin and methylated-β-cyclodextrin.The substituted groups in the rim of HP-β-cyclodextrin and methylated-β-cyclodextrin lead to weak aggregation.This research provided us a clear molecular mechanism of glipizide/cyclodextrin complexation and aggregation.This research will also benefit the formulation development of cyclodextrin solubilization.

Luminol-K_3Fe(CN)_6 chemiluminescence system for the determination of glipizide

A rapid and sensitive flow-injection chemiluminescence（CL） method for the determination of glipizide was developed on the basis of finding that glipizide can enhance the CL intensity of the luminol-K3Fe（CN）6 system.In optimum condition,the increased CL intensity was directly proportional to the concentration of glipizide in the range from 4.0×108 g/mL to 1.0×106 g/mL and the detection limit was 1.0×108 g/mL glipizide.The relative standard deviation（RSD） of the developed method was 2.1% with 11 repeated measurements of 1.0×107 g/mL glipizide.The developed method has been successfully applied to the analysis of glipizide in its pharmaceutical preparations.

Effect of raw material variability of glipizide on the in vitro dissolution rate and in vivo bioavailability performance: The importance of particle size

The objective of this study was to understand the impact of active pharmaceutical ingredients(API) particle size on a re-developed generic product of glipizide and to improve its formulation so that it exhibits bioequivalent to that of the reference listed drug(RLD). Two commercial batches of APIs(API-1 and API-2) with the same polymorphism and one batch of home-made APIs(API-3) with super-small particle size were used in the present study.The in vitro dissolution profiles of the tested formulations were compared with the RLD in a series of dissolution media. Then, the impact of particle size on in vivo absorption was evaluated in Beagle dogs. Compared with the RLD, formulation A with larger API size showed slower dissolution in p H 6.0 and 7.4 medium, resulting bioinequivalent with the RLD. Conversely, formulation B with smaller API size demonstrated similar in vitro dissolution profiles with the RLD and thus exhibited bioequivalent in the present study. Furthermore, formulation C with super small particle size still exhibited identical oral absorption although rapid dissolution was observed in the tested condition. Herein, it indicated that 2–5 μm might be defined as the "inert size range" of glipizide for ensuring the bioequivalence with the RLD. The results in the present study might help to obtain a better understanding of the variability in raw materials for oral absorption, develop a bioequivalent product and thus post-market quality control.

新型磺脲类口服降糖药Glipizide

Glipizidc系第二代磺脲类口服降糖药,化学结构为(N-[4-β-（5-甲基吡嗪-2-羧基酰胺-乙基-苯磺酰]-n-环已基脲）。由于环已基替代了脂族的一个侧链,并与甘氨酸结合,使其对胰岛β-细胞的亲和力增强100倍。该药于1971年在欧洲合成,适用于因饮食、锻炼不能有效控制血糖的非胰岛素依赖性糖尿病（NIDDM）,较氯磺苯脲、甲苯磺丁脲(D860)疗效更好,且可减少心血管并发症。最近,美国食品药物管理局（FDA）已批准在美国使用。

Pinacidil reduces neuronal apoptosis following cerebral ischemia-reperfusion in rats through both mitochondrial and death-receptor signal pathways

Objective To investigate effect of pinacidil, an ATP sensitive potassium channel （KATP） opener, on the neuronal apoptosis and its signaling transduction mechanism following focal cerebral ischemia-reperfusion in rats. Methods One hundred male Wistar rats were randomly divided into four groups： A, sham-operated group; B, ischemia-reperfusion group; C, KATe opener treatment group; and D, KATe opener and blocker treatment group. The middle cerebral artery occlusion （MCAO） model was established by using the intraluminal suture occlusion method, neuronal apoptosis was determined by TUNEL staining, and expressions of caspase-8, caspase-9 and caspase-3 mRNA were detected by in situ hybridization. Results （1） The numbers of apoptotic neurons at 12 h, 24 h, 48 h, and 72 h were significantly less in group C than in groups B and D （P 〈 0.01 or P 〈 0.05）; and there was no difference between groups B and D at all time points （P 〉 0.05）. （2） The expressions of caspase-3 mRNA and caspase-8 mRNA at all times and the expressions of caspase-9 mRNA at 12 h, 24 h, 48 h, 72 h were significantly lower in group C than in groups B and D （P 〈 0.01 or P 〈 0.05）; and there were no differences between groups B and D at all time points （P 〉 0.05）. Conclusions KATP opener can significantly decrease the neuronal apoptosis and the expressions of caspase-3, caspase-8 and caspase-9 mRNAs following cerebral ischemiareperfusion. The neuronal apoptosis may be decreased by the inhibition of both mitochondrial and death-receptor signal pathways.

Multi-dimensional visualization for the morphology of lubricant stearic acid particles and their distribution in tablets

The shapes of particles and their distribution in tablets, controlled by pretreatment and tableting process, determine the pharmaceutical performance of excipient like lubricant. This study aims to provide deeper insights to the relationship of the morphology and spatial distribution of stearic acid(SA) with the lubrication efficiency, as well as the resulting tablet property. Unmodified SA particles as flat sheet-like particles were firstly reprocessed by emulsification in hot water to obtain the reprocessed SA particles with spherical morphology. The three-dimensional(3 D) information of SA particles in tablets was detected by a quantitative and non-invasive 3 D structure elucidation technique, namely, synchrotron radiation X-ray micro-computed tomography(SR-μCT). SA particles in glipizide tablets prepared by using unmodified SA(GUT), reprocessed SA(GRT), as well as reference listed drug(RLD) of glipizide tablets were analyzed by SR-μCT. The results showed that the reprocessed SA with better flowability contributed to similarity of breaking forces between that of GRT and RLD. SA particles in GRT were very similar to those in RLD with uniform morphology and particle size, while SA particles in GUT were not evenly distributed. These findings not only demonstrated the feasibility of SR-μCT as a new method in revealing the morphology and spatial distribution of excipient in drug delivery system, but also deepened insights of solid dosage form design into a new scale by powder engineering.

Liquid Chromatography-electrospray Ionization Tandem Mass Spectrometry for Simultaneous Determination of Metformin and Glimepiride in Beagle Dog Plasma and Bioequivalence Study

A sensitive and selective liquid chromatography-electrospray ionization tandem mass spectrometry（LC- ES1-MS/MS） was used for the simultaneous determination of metformin and glimepiride in beagle dog plasma with glipizide as internal standard（IS）. After simplified protein precipitation with methanol, both the analytes and IS were chromatographed on a Zorbax CN column via gradient elution with methanol（containing 5 mmol/L ammonium ace- tate） and 5 mmol/L aqueous ammonium acetate as the mobile phase. Detection was performed by multiple reaction monitoring（MRM） scanning via ESI source operated in positive ionization mode. Specificity, linearity, accuracy, pre- cision, recovery, matrix effect and stability were validated for metformin and glimepiride in beagle dog plasma. The calibration curves were linear in a concentration range of 10-10000 ng/mL for metformin and 4-4000 ng/mL for glimepiride with both correlation coefficients higher than 0.99. The recoveries obtained for the analytes and IS were all between 82.7% and 101.2%. The method exhibited excellent performance in terms of selectivity, robustness, short analytical time and simplicity of sample preparation. Finally, the proposed method was applied to a bioequivalence study of self-made bilayer tablet and commercial formulation containing 500 mg of metformin and 1 mg of glimepi- ride in beagle dogs.

Inhibition Performance of Some Sulfonylurea on Copper Corrosion in Nitric Acid Solution Evaluated Theoretically by DFT Calculations

The theoretical study of chlorpropamide, tolazamide and glipizide was carried out by the Density Functional Theory (DFT) at B3LYP/6-31G(d) level. This study made it possible to determine the global reactivity parameters in order to better understand the interactions between the molecules studied and the copper surface. Then, the determination of local reactivity indices (Fukui functions and dual descriptor) on these molecules resulted in the precision on the most probable centers of nucleophilic and electrophilic attacks within each molecule. The results obtained, show that chloropropamide, tolazamide and glipizide can be good inhibitors against copper corrosion. Thus, the mechanism of copper corrosion inhibition of these compounds in nitric acid solution has been explained by means of theoretical calculations.

Comparative Review of Drugs Used in Diabetes Mellitus—New and Old

Background: Diabetes mellitus (DM) is a syndrome of chronically elevated glucose level in the blood either due to insulin resistance, insulin deficiency or both. In addition, it may occur due to defective metabolism of carbohydrates, fats and proteins. There are 3 main types of DM: Type 2 DM is more prevalent in adults and is typically due to relative insulin deficiency, deficiency of insulin in children leads to DM type 1;and lastly, gestational diabetes occurs during pregnancy resulting from an imbalance of placental hormones. Introduction: Insulin, Biguanides and Sulfonylureas are some of the drug classes used to treat DM. However, their use is complicated by numerous side effects, such as;hypoglycemia & weight gain from insulin and sulfonylureas;lactic acidosis, vitamin B12 deficiency and gastrointestinal upset with metformin. Route of administration and cost are also important factors to consider when prescribing. It is for this reason the quest for newer, safer and easier to administer drugs is ongoing. Methodology: Used all the articles available on anti Diabetic drugs on web especially in British Medical Journal, Elsevier, Pubmed, Google scholar and Wikipedia etc. Got a final review article to compare the older and newer anti Diabetic drugs. Results and Conclusion: Insulin is good for controlling acute hyperglycemic states in DM but it causes acute hypoglycemia and lipodystrophy. Metformin is good hypoglycemic and easily available but causes hypoglycemia, metallic taste, Lactic acidosis and B12 deficiency. Sulfonylureas are good hypoglycemic but causes severe hypoglycemia acutely and weight gain so contraindicated for obese or hypertensive patients. While newer antidiabetics such as GLP 1 agonists increases insulin secretions has very low risk of hypoglycemia, causes weight loss as compared to insulin and decreases risk of cardiovascular side effects but still can’t be used in renally impaired patients, causes pancreatitis and can not be given in gastroparesis patients, similarly a newer drug of this class known as LY2189265 has long halflife of 90 hours, better efficacy, but causes pancreatitis and increase diastolic BP in high doses, pancreatitis is not associated with lixisenatide (GLP 1 agonist), while DPP4 inhibitors which increases GLP 1 in body has less risk of hypoglycemia, GI side effects, are weight neutral can be used in CKD but causes headaches and Nasopharyngitis. Bromocriptine or pegvisomant are used in patients of growth hormones adenoma induced DM as a medical therapy but are associated with psychosis and hallucinations. Meglitinides increases insulin secretion and has minuscule risk of hypoglycemia but can not be used in CKD patients. Otelixizumab and Teplizumab decrease T cell functions and save beta cells from immune reactions used in DM 1 but cause immune suppression and is an orphan drug. Recombinant GAD used in vaccines decreased antibody mediated beta cell damage but is still under studies.